INDUCTION OF DELAYED HYPERSENSITIVITY TO SIV

开发一种安全有效的艾滋病毒疫苗是一个 艰巨的任务。抗体和细胞毒性T细胞对 HIV是在感染过程中产生的，但这些反应不能 最终控制感染或防止进展为致命 大多数感染者存在免疫缺陷。这 表明有一个被感染的细胞的储存库 被这两种经典的抗病毒免疫识别或消除 机械装置。我们假设一种新的免疫反应，一 在自然感染期间没有被诱导的，可能是有效的 作为疫苗诱导的免疫机制，给接种疫苗的人 在暴露前安装额外的抗病毒效应器装置 为艾滋病毒干杯。这种候选免疫反应，延迟型 超敏反应(DTH)，是控制免疫反应的关键 其他病毒和细胞内细菌感染，特别是在 人类感染结核病和麻风病。使用 SIV/猕猴HIV感染与艾滋病动物模型的研究目标 这一小笔研究拨款提案的目的是诱导潜伏期反应 对恒河猴体内的SIV抗原。SIV抗原致敏的树突状细胞 细胞将被用来引导效应器对DTH的反应。一个 将开发体外培养系统来模拟迟发型超敏反应 作为恒河猴生殖性SIV感染控制的反应 单核/巨噬细胞由自体、免疫T细胞产生。IF抗原 在免疫中检测到特异性和MHC限制性反应 动物，它们将受到粘膜接种的挑战 致病性SIVmac251。将对挑战的结果进行评估 通过定量病毒载量测量，抗病毒免疫 组织的反应和病理变化。如果抗病毒DTH是一种 对SIV的保护性免疫反应，显著减少病毒 感染急性期的负荷、增强的DTH和CTL 应答和延迟中和抗体应答 预期中。此外，播散性SIV的病理变化 外周淋巴组织感染应显著 减少了。这些结果将支持抗病毒的概念 迟发型超敏反应作为一种针对新型HIV靶的保护性免疫反应 疫苗。

The development of a safe and effective HIV vaccine is a formidable task. Both antibody and cytotoxic T cell responses to HIV are generated during the infection, but these responses cannot ultimately control the infection or prevent progression to fatal immunodeficiency in the majority of infected individuals. This suggests that there is a reservoir of infected cells that are not recognized or eliminated by these two classical antiviral immune mechanisms. We hypothesize that a novel immune response, one that is not induced during the natural infection, could be effective as a vaccine - induced immune mechanism, giving the vaccinated host an additional antiviral effector mechanism prior to exposure to HIV. This candidate immune response, delayed type hypersensitivity (DTH), is a key controlling immune response in other viral and intracellular bacterial infections, particularly in human infections with tuberculosis and leprosy. Using the SIV/macaque animal model of HIV infection and AIDS, the goal of this small research grant proposal is to induce a DTH response to SIV antigens in rhesus monkeys. SIv antigen-pulsed dendritic cells will be used to direct the effector response toward DTH. An in vitro culture system will be developed to model the DTH response as the control of productive SIV infection in rhesus monocyte/macrophage by autologous, immune T cells. If antigen specific and MHC-restricted responses are detected in immunized animals, they will be challenged by mucosal inoculation of pathogenic SIVmac251. The outcome of challenge will be assessed by quantitative viral load measurements, antiviral immune responses and pathologicchanges in tissues. If antiviral DTH is a protective immune response to SIV, significant reduction in viral load during the acute stage of infection, enhanced DTH and CTL responses and a delayed neutralizing antibody response are expected. In addition, the pathologic changes of disseminated SIV infection in peripheral lymphoid tissues should be significantly reduced. These outcomes would support the concept of antiviral DTH as a protective immune response to target with a novel HIV vaccine.